Quantitative determination of CGS 26214, a cholesterol lowering agent, in human plasma using negative electrospray ionization liquid chromatography-tandem mass spectrometry

CGS 26214 is a synthetic cholesterol-lowering agent shown to be active in t he rat, dog and monkey. The present work was conducted to develop a sensiti ve liquid chromatography-tandem mass spectrometry (LC-MS-MS) method for qua ntitative determination of the compound in human plasma following clinical doses of 10-100 mug per day. A number of analytical challenges were encount ered during the development of the assay. The compound was an eater and sus ceptible to hydrolysis under experimental conditions. A lower limit of quan titation of 50 pg/ml was needed due to the low clinical doses. Positive ele ctrospray ionization of CGS 26214 yielded insufficient sensitivity needed f or the studies. Consequently, LC-MS-MS conditions were optimized for the ne gative ion mode of detection. The sample preparation steps proved to be cri tical in order to reduce the possibility of microbore column (50 mmX 1.0 mm I.D.) obstruction, chromatographic deterioration, and matrix mediated elec trospray ion suppression. The present method addressed the above issues. Th e method was accurate and reproducible and was successfully applied to gene rate plasma concentration-time profiles for human subjects after low oral d oses of the compound. (C) 2001 Elsevier Science B.V. All rights reserved.